722500-60-9Relevant academic research and scientific papers
Development of a Nucleotide Exchange Inhibitor That Impairs Ras Oncogenic Signaling
Marín-Ramos, Nagore I.,Pi?ar, Carmen,Vázquez-Villa, Henar,Martín-Fontecha, Mar,González, ángel,Canales, ángeles,Algar, Sergio,Mayo, Paloma P.,Jiménez-Barbero, Jesús,Gajate, Consuelo,Mollinedo, Faustino,Pardo, Leonardo,Ortega-Gutiérrez, Silvia,Viso, Alma,López-Rodríguez, María L.
supporting information, p. 1676 - 1685 (2017/02/10)
Despite more than three decades of intense effort, no anti-Ras therapies have reached clinical application. Contributing to this failure has been an underestimation of Ras complexity and a dearth of structural information. In this regard, recent studies have revealed the highly dynamic character of the Ras surface and the existence of transient pockets suitable for small-molecule binding, opening up new possibilities for the development of Ras modulators. Herein, a novel Ras inhibitor (compound 12) is described that selectively impairs mutated Ras activity in a reversible manner without significantly affecting wild-type Ras, reduces the Ras–guanosine triphosphate (GTP) levels, inhibits the activation of the mitogen-activated protein kinase (MAPK) pathway, and exhibits remarkable cytotoxic activity in Ras-driven cellular models. The use of molecular dynamics simulations and NMR spectroscopy experiments has enabled the molecular bases responsible for the interactions between compound 12 and Ras protein to be explored. The new Ras inhibitor binds partially to the GTP-binding region and extends into the adjacent hydrophobic pocket delimited by switch II. Hence, Ras inhibitor 12 could represent a new compound for the development of more efficacious drugs to target Ras-driven cancers; a currently unmet clinical need.
Synthesis of kojic acid derivatives as secondary binding site probes of d-amino acid oxidase
Raje, Mithun,Hin, Niyada,Duvall, Bridget,Ferraris, Dana V.,Berry, James F.,Thomas, Ajit G.,Alt, Jesse,Rojas, Camilo,Slusher, Barbara S.,Tsukamoto, Takashi
supporting information, p. 3910 - 3913 (2013/07/25)
A series of kojic acid (5-hydroxy-2-hydroxymethyl-4H-pyran-4-one) derivatives were synthesized and tested for their ability to inhibit d-amino acid oxidase (DAAO). Various substituents were incorporated into kojic acid at its 2-hydroxymethyl group. These
The monoethyl ester of meconic acid is an active site inhibitor of HCV NS5B RNA-dependent RNA polymerase
Pace, Paola,Nizi, Emanuela,Pacini, Barbara,Pesci, Silvia,Matassa, Victor,De Francesco, Raffaele,Altamura, Sergio,Summa, Vincenzo
, p. 3257 - 3261 (2007/10/03)
Screening of the in-house sample collection for compounds with HCV NS5B RNA dependent RNA polymerase inhibition led to the identification of a new lead. Afterwards, we discovered that the screening lead, rather than containing the expected structure 1, was comprised of roughly a 1:1 mixture of meconic acid 2 and its monoethyl ester 3, with all inhibitory potency residing with 3. We propose that this compound shares critical common features for activity with α,γ-diketoacids inhibitors previously discovered by our group. SAR around this molecule will be presented to provide an improved basis for structure-based ligand design.
